The Host STING Pathway at the Interface of Cancer and Immunity

J Clin Invest. 2016 Jul 1;126(7):2404-11. doi: 10.1172/JCI86892. Epub 2016 Jul 1.

Abstract

A major subset of human cancers shows evidence for spontaneous adaptive immunity, which is reflected by the presence of infiltrating CD8+ T cells specific for tumor antigens within the tumor microenvironment. This observation has raised the question of which innate immune sensing pathway might detect the presence of cancer and lead to a natural adaptive antitumor immune response in the absence of exogenous infectious pathogens. Evidence for a critical functional role for type I IFNs led to interrogation of candidate innate immune sensing pathways that might be triggered by tumor presence and induce type I IFN production. Such analyses have revealed a major role for the stimulator of IFN genes pathway (STING pathway), which senses cytosolic tumor-derived DNA within the cytosol of tumor-infiltrating DCs. Activation of this pathway is correlated with IFN-β production and induction of antitumor T cells. Based on the biology of this natural immune response, pharmacologic agonists of the STING pathway are being developed to augment and optimize STING activation as a cancer therapy. Intratumoral administration of STING agonists results in remarkable therapeutic activity in mouse models, and STING agonists are being carried forward into phase I clinical testing.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antigen-Presenting Cells / immunology
  • Antineoplastic Agents / pharmacology
  • CD8-Positive T-Lymphocytes / cytology
  • Cytosol / metabolism
  • DNA, Neoplasm / analysis
  • Dendritic Cells / immunology
  • Humans
  • Immunity, Innate
  • Interferon-beta / immunology
  • Interferons / immunology*
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Tumor Microenvironment / immunology

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Interferon-beta
  • Interferons